Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus. It was first identified by its antifungal activity but has been more often studied as an immunosuppressive agent. ##STR1##
A large number of structural variants of rapamycin have been reported, typically arising as alternative fermentation products or from synthetic efforts to improve the compound's therapeutic index as an immunosuppressive agent. For example, the extensive literature on analogs, homologs, derivatives and other compounds related structurally to rapamycin ("rapalogs") include among others variants of rapamycin having one or more of the following modifications relative to rapamycin: demethylation, elimination or replacement of the methoxy at C7, C42 and/or C29; elimination, derivatization or replacement of the hydroxy at C13, C43 and/or C28; reduction, elimination or derivatization of the ketone at C14, C24 and/or C30; replacement of the 6-membered pipecolate ring with a 5-membered prolyl ring; and alternative substitution on the cyclohexyl ring or replacement of the cyclohexyl ring with a substituted cyclopentyl ring. In nearly all cases, potent immunosuppressive activity is reported to accompany antifungal activity of the rapalogs. Additional historical information is presented in the background sections of U.S. Pat. Nos. 5,525,610; 5,310,903 and 5,362,718.
U.S. Pat. No. 5,527,907 is illustrative of the patent literature. That document discloses a series of compounds which were synthesized in an effort to make immunosuppressant rapalogs with reduced side effects. The compounds are disclosed via seven Markush structures, each followed by two to five or more columns of text listing possible substituents at various positions on the rapamycin ring. The document includes over 180 synthetic examples. The many variants of that invention were reported to be potent immunosuppressive agents.
While rapamycin is known to adversely affect the growth of fungi such as Candida albicans and Microsporum gypseum, its potent immunosuppressive activity renders it an unlikely
This application claim benefit to provisional application 00/021,624 Jul. 12, 1996 which claims benefit to provisional application 00/042,307 May 30, 1997 candidate for use as an antifungal agent. Even some of the more recent patent documents such as WO 94/02136 (SmithKline Beecham), WO 95/16691 (Sandoz), U.S. Pat. No. 5,583,139 (Abbott) and U.S. Pat. No. 5,527,907 (Abbott), despite their extensive sets of structural modifications to rapamycin, fail to suggest even the possibility of reducing rapamycin's immunosuppressive activity without sacrificing its antifungal activity--let alone any structural approach for doing so--as would be desired or required in an antifungal agent. Indeed, the expectation that optimal response to any antifungal agent would require an active immune system in the treated patient appears to rule out the use of a rapalog. Thus it is not surprising that there are no known reports of the clinical development of rapamycin or a rapalog for treating or preventing infection by a pathogenic fungus in humans or other animals.
Meanwhile, although pathogenic fungi represent an increasing clinical challenge, existing antifungal agents are hampered by issues of efficacy, toxicity and the development and/or discovery of strains of pathogenic fungi that are resistant to drugs currently available or under development. By way of example, fungi that are pathogenic in humans include among others Candida spp. including C. albicans, C. tropicalis, C. kerr, C. krusei and C. galbrata; Aspergillus spp. including A. fumigatus and A. flavus; Cryptococcus neofornans; Blastomyces spp. including Blastomyces dermatitidis; Pneumocystis carinii; Coccidioides immitis; Basidiobolus ranarum; Conidiobolus spp.; Histoplasma capsulatum; Rhizopus spp. including R. oryzae and R. microsporus; Cunninghamella spp.; Rhizomucor spp.; Paracoccidioides brasiliensis; Pseudallescheria boydii; Rhinosporidium seeberi; and Sporothrix schenckii [Kwon-Chung, K. J. and Bennett, J. E. (1992): Medical Mycology (Lea and Febiger, Malvern, Pa.)].
As described by Turner and Rodriguez, 1996, Current Pharmaceutical Design, 2, 209-224:
The need for new antifungal agents has never been greater. Over the past ten years the incidence of life-threatening fungal infections has increased dramatically as the population of immunocompromised individuals including cancer, organ transplant, and AIDS patients has increased. PA1 Also contributing to this risk is the increased use of broad-spectrum antibiotics, increased use of invasive medical techniques, and an aging patient population.
While there is little in the literature to suggest the feasibility of any pharmaceutical approach for harnessing the antifungal activity of rapamycin or the rapalogs, non-immunosuppressive derivatives of rapamycin that retain anti-fungal activity would be of great interest for the treatment or prevention of pathogenic fungal infection.